The purpose of the research program is to discover new anti-HIV drugs that are potent, safe, and easily administered. The approach combines state-of-the-art technology for molecular design, synthetic organic chemistry, biological assaying, and crystallographic determination of structures of the designed molecules bound to their protein target. The PI's research program spans fundamental advances in the development of software and methodology, detailed modeling of protein-ligand binding, inhibitor design, and small-molecule synthesis. Collaborations provide the determinations of biological activity in human T-cells and macromolecular structures. The PI's group has developed computational tools to speed lead optimization for potency, while being mindful of the need for desirable pharmacological properties. The specific focus is the discovery of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). NNRTIs are a central component of highly active antiretroviral therapy (HAART) in spite of significant deficiencies in the currently approved drugs in this class. The previous grant period witnessed striking advances for several chemical series including discovery of the most potent NNRTI ever reported for wild-type (WT) HIV-1. Means to enhance aqueous solubility, which has been problematic for most NNRTIs, also emerged. Building from these discoveries, new efforts are focused on advancing compounds from four chemical series into preclinical development. Catechol diethers are being further optimized to replace a cyanovinylphenyl group, which is a safety concern, with a substituted bicyclic heterocycle. In addition to the safety benefit, molecular modeling indicates that the new analogues should show enhanced anti-HIV activity. In addition, diarylamines and the catechol diethers are being modified with addition of a morpholinylalkoxy side chain that is strategically positioned to avoid significant reduction in potency, while providing a ca. 100-fold increase in aqueous solubility. Minor modifications of the solubilized diarylamines appear needed to yield preclinical candidates. Advances in a series containing an oxazole ring have also been made to provide excellent potency towards WT HIV-1 and the clinically important Tyr181Cys containing variant strain. In depth computational analysis led to a nearly 60- fold gain in potency towards the Tyr181Cys variant while retaining 5-nM potency towards the WT virus. Similar analyses are being carried out for the other prominent clinical variant, Lys103Asn; only a ca. 10-fold gain is needed to bring the potency towards strains with this replacement to the 10-nM level.